1. Better Developmental function at 3 years for infants born at 22-23wks who participated in the Randomized Controlled Trial for the Prevention of Intraventricular Hemorrhage by Indomethacin in Japanese Extremely Low Birthweight Infants SHINYA HIRANO, M.D. 1 ） MASANORI FUJIMURA, M.D. 1 ） Neonatal Research Network Japan 1 ） Department of Neonatal Medicine, Osaka Medical Center for Maternal and Child Health, Izumi, Osaka, Japan.

2. Has documented that he/she has no financial relationships to disclose or Conflicts of Interest (COIs) to resolve. SHINYA HIRANO

3. 【 Subjects 】 To fulfill all of the following; Birth weight: 400g-999g Gestation: 22 weeks 0 day ≤ 24 weeks ≤ & birth weight standard deviation -2.0< 【 Method 】 Starting within 6 hours of birth 3 doses of IND or placebo were given with 6 hours continuous i.v. infusion every 24 hours. IND was given at the dose of 0.1 mg/kg-wt/dose. 【 Outcomes 】 Primary : IVH Grade III or IV within 7days Secondary : Cerebral palsy, DQ at 3 year of age Indomethacin Trial

4. 718 infants assessed for eligibility 50 : Excluded 67 : Not approached 469 infants 235 IND 234 placebo 132 : No consent 601 infants eligible Death : 22 Drop out, No data : 22 Death : 29 Drop out, No data : 18 191187 378 / 418 (90.4%) Stratified factors Institution G.W Sex In- / Out-born Apgar at 1min

5. IVH Grade III or IV within 7days INDPlacebo 16 / 235 (6.8%)32 / 234 (13.7%) odds ratio (95% CI) 0.37 (0.18-0.77) effective to prevent severe Intraventricular hemorrhage (IVH) (2005 SPR)

6. Cerebral palsy and/or Death around 3 years INDPlacebo odds ratio (95% CI) Death 22/235 (9%) 29/234 (12.4%) 0.75 (0.4-1.4) Cerebral Palsy 31/235 (13.2%) 32/234 (13.7%) 0.95 (0.54-1.69) Cerebral Palsy or Death 53/235 (22.5%) 61/234 (26.0%) 0.82 (0.53-1.29) did not reduce the incidence of CP and/or Death (2008 SPR/ASPR)

7. IVH III or IV CP or Death INDPlaceboINDPlacebo Odds ratio(95% CI) 400-599g 2/2211/277/2218/27 0.14 (0.01-0.84)0.23 (0.05-0.89) 600-899g 12/16419/15039/16434/150 0.58 (0.25-1.32)1.06 (0.60-1.86) 900-999g 2/492/577/499/57 1.17 (0.08-16.7)0.88 (0.25-2.95) Incidence of IVH Grede III or IV and “CP or Death “ stratified by Birth weight group the incidence of “severe IVH” and “CP or death” significantly reduced in 400-599g (2008 SPR/ASPR)

8. IVH III or IV CP or Death INDPlaceboINDPlacebo Odds ratio (95% CI) 22-23w 3 / 2311 / 229 / 2315 / 22 0.15 (0.02-0.76)0.3 (0.073-1.19) 24-26w 13 / 13624 / 13535 / 13639 / 135 0.49 (0.22-1.06)0.85 (0.48-1.51) 27w- 1 / 762 / 769 / 767 / 77 0.49 (0.01-9.71)1.34 (0.42-4.50) Stratified by gestational weeks Seem to be effective to reduce “severe IVH” and “CP or death” in 22-23wks (2008 SPR/ASPR)

9. 【 Objective 】 To compare the developmental quotient (DQ) using the Kyoto Scale of Psychological Development (KSPD) at 3 years between the two groups (IND or placebo) in follow-up study.

10. The KSPD (the kyoto scale of psychological development) : a standardized developmental function assessment tool for Japanese infants widely used at child counseling centers and at public health centers expressed as the developmental age (DA) for three areas Cognitive-Adaptive (C-A) Language-Social (L-S) Postural-Motor (P-M) Total score ; adding up for the three areas DQ: calculated dividing the DA by chronological age, then multiplied by 100

11. Death : 22 Drop out or no data: 22 IND 235 Placebo 234 Death : 29 Drop out or no data: 18 191 187 171 160 469 Kyoto Scale of Psychological Development (KSPD) at 3 years ()

12. IND (N=171) Placebo (N=160) p Birthwight (g) 790.9±130.4807.9±788.5 0.23 G.W.(w) 26.2±1.526.4±1.6 0.12 Apgar 5min 6.8 ±1.97.0 ±1.9 0.20 primipara89 (52.1%)77 (48.1%) 0.51 singleton136 (79.5%)122 (76.3%) 0.51 Vaginal delivery42 (24.6%)40 (25.0%) 1.0 Mean±1SD Baseline Characteristics 1

13. IND (N=171) Placebo (N=160) p Maternal steroid 79 (46.2%)75 (46.9%) 0.78 Birth weight <-1.5 SD 24 (14.0%) 25 (15.6%) 0.75 RDS 133 (77.8%)132 (82.5%) 0.34 Pneumothorax 3 (1.8%)3 (1.9%) 1.0 IVH 3 or 4 12 (7.0%)9 (5.6%) 0.65 CP 24 (14.0%)19 (11.9%) 0.62 Baseline Characteristics 2

14. Total Score Postural- Motor Cognitive- Adaptive Language- Social P=0.09P=0.16P=0.10P=0.38 Comparison of KSPD -DQ 171 160 161157168 161 168 161

15. p=0.92 p=0.26 p=0.16 400-599g600-899g900-999g Comparison of Total Score DQ - by Birthweight group 1410115107 42 43

16. 22-23W24-26W27W- p=0.042 p=0.06 p=0.06 12 9101 88 67 72 Comparison of Total Score DQ -categorized by G.W.

17. IND (N=12) Placebo (N=9) p Birthweight (g) 598.3±90.0574±102.9 0.57 Gestational Weeks(w) 23.3±0.3723.2±0.45 0.43 Apgar 5min 6.3±1.56.4±2.1 0.80 primipara 6 (50%)1 (11.1%) 0.16 singleton 11 (91.7%)8 (88.9%) 1.0 Maternal steroid 3 (25%)4 (44.4%) 0.40 RDS 10 (83.3%)9 (100%) Male 5 (2.4%)6 (66.6%) 0.39 IVH grade 3 or 4 1 (8.3%)2 (22.2%) 0.55 CP 5 (41.7%)4 (44.4%) 1.0 Mean±SD 22 － 23w Baseline Characteristics

18. Conclusions: 1.There was no significant difference of DQ for all areas at 3 years evaluated by KSPD between IND and Placebo group in a large RCT in Japan. 2. In secondly analysis using the category of GW and Birthweight, DQ of IND group was significantly higher than that of Placebo group in 22-23GW group. 3. We have shown that Prophylactic use of indomethacin for prevention of IVH is effective in reducing CP and improving DQ for 22-23GW Japanese infants.

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